Format

Send to

Choose Destination
Nature. 2016 Feb 4;530(7588):108-12. doi: 10.1038/nature16465. Epub 2016 Jan 27.

An essential receptor for adeno-associated virus infection.

Author information

1
Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Drive, Stanford, California 94305, USA.
2
Department of Biochemistry and Molecular Biology, School of Medicine, Oregon Health &Science University, 3181 Sam Jackson Park Road, Portland, Oregon 97239-3098, USA.
3
Shriners Hospital for Children, 3101 Sam Jackson Park Road, Portland, Oregon 97239, USA.
4
Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands.
5
Department of Comparative Medicine, Stanford University School of Medicine, 287 Campus Drive, Stanford, California 94305, USA.

Abstract

Adeno-associated virus (AAV) vectors are currently the leading candidates for virus-based gene therapies because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. They have been successfully used in clinical trials to treat hereditary diseases such as haemophilia B (ref. 2), and have been approved for treatment of lipoprotein lipase deficiency in Europe. Considerable efforts have been made to engineer AAV variants with novel and biomedically valuable cell tropisms to allow efficacious systemic administration, yet basic aspects of AAV cellular entry are still poorly understood. In particular, the protein receptor(s) required for AAV entry after cell attachment remains unknown. Here we use an unbiased genetic screen to identify proteins essential for AAV serotype 2 (AAV2) infection in a haploid human cell line. The most significantly enriched gene of the screen encodes a previously uncharacterized type I transmembrane protein, KIAA0319L (denoted hereafter as AAV receptor (AAVR)). We characterize AAVR as a protein capable of rapid endocytosis from the plasma membrane and trafficking to the trans-Golgi network. We show that AAVR directly binds to AAV2 particles, and that anti-AAVR antibodies efficiently block AAV2 infection. Moreover, genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV2 infection. Notably, AAVR serves as a critical host factor for all tested AAV serotypes. The importance of AAVR for in vivo gene delivery is further highlighted by the robust resistance of Aavr(-/-) (also known as Au040320(-/-) and Kiaa0319l(-/-)) mice to AAV infection. Collectively, our data indicate that AAVR is a universal receptor involved in AAV infection.

Comment in

PMID:
26814968
PMCID:
PMC4962915
DOI:
10.1038/nature16465
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center